Simvastatin, a cholesterol-lowering agent, is chemically designated as butanoic acid, 2,2-dimethyl-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-napthalenyl ester, [1S-[1α,3α,7β,8β(2S*, 4S*),-8a β. Simvastatin dihydroxy acid is a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme (HMG-CoA) reductase, which catalyzes the rate-limiting step conversion of HMG-CoA to mevalonate in cholesterol synthesis. Simvastatin is sold under the tradename ZOCOR® and is marketed by Merck & Co., Inc. There is a need for a high yield and efficient commercial scale processes for preparing simvastatin.
U.S. Pat. No. 4,444,784 describes heating the dihydroxy acid in neutral solvent with continuous removal of the water by-product in order to drive the equilibrium reaction toward lactone formation. However, heating promotes an undesirable esterification reaction between the 3-hydroxy group of the 3-hydroxylactone with the precursor free acid to increase the amount of dimer.
PCT/EP 98/00519 describes preparing simvastatin with a low level of dimer impurity. The lactonization process uses the ammonium salt of simvastatin as the starting material and involves refluxing in toluene followed by crystallizations to obtain pure simvastatin. The simvastatin prepared in accordance with this procedure is found to have a low dimer content of about 0.1 to about 0.12% wt.
Lactonization reaction of simvastatin ammonium salt to simvastatin is an equilibrium reaction which is illustrated as follows: 
Lactonization as an intramolecular esterification can be accompanied by the esterification of the reaction product with starting material present in the reaction mixture. This intermolecular esterification leads to the formation of simvastatin dimer byproduct having the structure shown in the scheme above.
The European and U.S. pharmaceutical industry standards for certain simvastatin products requires that simvastatin cannot contain more than 0.4% wt dimer. This relatively high amount of impurity accepted by pharmaceutical authorities may be due to the understanding that not only simvastatin but also the simvastatin dimer are precursors of the pharmacologically active dihydroxy open acid form of the compound (PCT/US 01/27466).
Efforts to produce simvastatin containing less than 0.2% of the simvastatin dimer have been made. EP 351 918 discloses a method for acid catalyzed lactonization leading to a simvastatin crude product containing less than 0.2% wt of simvastatin dimer. This reference discloses that attempts to produce simvastatin of this quality by purification had failed.
For other applications, it is desirable that purified simvastatin active ingredient contain about 0.2 to about 0.4% wt simvastatin dimer; more preferably, about 0.25 to about 0.34% wt. Accordingly, a reproducible process for preparing simvastatin active ingredient having a controllable dimer content in the specified ranges, as well as acceptable impurity profile, is desirable.